Phage Therapy: The answer to multidrug resistant bacteria

By John Garza

One of the major issues facing modern medicine is the rising prevalence of multidrug resistant bacteria. Most of the current strategies for dealing with this problem are preventative: minimizing the number of people infected, stopping the spread of the resistant pathogens, tracking them when they do crop up, and using antibiotics more responsibly. For those who do have the misfortune of contracting a resistant illness, treatment relies on identifying the microorganism responsible and selecting antibiotics to which it is still vulnerable. As resistance continues to increase in severity among disease-causing bacteria, it seems that the only hope for treatment lies in finding new antibiotics. This strategy has worked — so far.

A classic example is MRSA (methicillin-resistant Staphylococcus aureus), a resistant strain of a relatively common bacterium responsible for many hospital-acquired infections. When it first began to spread, a wide variety of frontline drugs were found to be ineffective in treating it; luckily, an older antibiotic, vancomycin, was successful. MRSA eventually began to develop resistance to vancomycin as well, but by then researchers had had enough time to develop new drugs, such as linezolid and quinupristin/dalfopristin.

However, new strains of multidrug resistant bacteria are beginning to emerge, and antibiotic development is no longer progressing at the rate it was when MRSA emerged. From 2008 to 2012, only 2 new drugs were approved by the FDA; a startling drop from the 16 approvals in the period from 1983 to 1987. There are three main reasons for the stagnation of antibiotic development. First, the most easily identified agents have already been identified, meaning that each successive generation of drugs developed requires more in depth research, funding, and time. Second, pharmaceutical companies find that short-course antibiotics have poor returns relative to drugs for chronic conditions. Lastly, FDA regulations have become increasingly impractical and confusing. In light of the potential failure of antibiotics in treating multidrug resistant diseases, an older alternative is coming to light: phage therapy.

Bacteriophages, often just called phages, are a class of viruses that exclusively infect bacteria. They spread by injecting their genetic material into a bacterium and hijacking the host’s own cellular machinery to multiply rapidly; this continues until the cell bursts, killing the host and releasing the next generation of phages to infect more bacteria. Phages were first discovered about a century ago in Europe, when their disease-fighting properties were noted. It was soon discovered that people with certain diseases could be deliberately exposed to phage “infections” to cure their illness. This was the start of phage therapy.

Research into phage therapy quickly grew in Eastern Europe. However, a combination of factors led to it never becoming prevalent outside this region. In the initial years, inconsistent results made many scientists wary to pursue a still poorly understood mechanism of disease treatment. Nearly simultaneously, the miraculous development of antibiotics exploded and drew much more attention than phage therapy ever did. Following this, the outbreak of World War II broke lines of communication in both directions: the Western world turned to antibiotics, while many Soviet states used phage therapy instead. To this day, phage therapy remains important in Russia, Georgia, and Poland.

As the Western world is coming to realize, phage therapy has several advantages over antibiotics. Antibiotics are static chemicals, whereas the microorganisms they target are living creatures capable of mutation; this is the principal mechanism of resistance. On the other hand, phages are capable of evolving in tandem with their intended targets, so resistance via mutation would be less of a concern. Even if a strain of bacteria does manage to become immune to the phages intended to attack it, another can always be selected — there are an estimated 1031 phages on the planet, all potentially capable of treating a disease. (For comparison, there are “only” 1024 stars in the observable universe!)

Another important point to note is the recent trend in biomedical sciences that shows that our bodies harbor a great number of beneficial bacteria, known as our microbiome or microbiota. Perhaps the most important subset is our gut microbiota. These bacteria supply essential nutrients, break down indigestible substances, support and strengthen our immune system, and help prevent infection from harmful bacteria. Modern antibiotics tend to be broad-spectrum, harming not just the illness-causing bacteria but also the beneficial bacteria native to our bodies. When these bacteria experience die-offs, they leave us vulnerable to colonization by disease-causing bacteria. By contrast, phages target one species of bacteria at a time.

It seems as though phages might be another miracle solution, akin to the discovery of antibiotics — but there are some obstacles slowing or preventing the development of phage therapy. As mentioned previously, phages are capable of evolving; while this usually allows them to keep up with resistance mutations in their bacterial hosts, it is theoretically possible that they could acquire mutations that are harmful to humans. Additionally, in a process known as lateral gene transfer, phages may acquire genes from other phages or even from bacteria. Phage-phage gene swapping could create novel substances that trigger immune reactions, while phage-bacteria gene swapping could allow the phage to gain genes responsible for virulence.

The FDA has strict guidelines for conducting trials to determine the viability of phage therapy; regulations are a major hurdle to bypass. One rule is that each individual phage or mixture of phages must go through its own clinical trial. However, since many human infections harbor multiple bacterial species, and phage therapy often includes multiple strains of phage per each individual target species, treatment is usually a custom-prepared blend of hundreds of phages for each patient, so it is impossible to test all possible combinations of phages, making this regulation a huge stumbling block. Another issue is the age of phage therapy. As it is nearly a century old, it is unlikely that a pharmaceutical company would be able to patent any phage treatment, leaving them with no guarantee that they could recoup costs, let alone make a profit.

As drug resistance in pathogenic bacteria continues its upward trend, our healthcare system will be forced to confront the rising threat. Our decision to delve more deeply into the possibilities presented by phage therapy, or to forge onwards in our attempts to discover and develop new antibiotics, will certainly have a large impact on the field of medicine into the foreseeable future.

Doctors are turning to a 100-year-old therapy that harnesses viruses to kill drug-resistant bacteria after the approach was recently used as a last-ditch effort to save a California man’s life.

It’s called bacteriophage therapy, and it uses a unique cocktail of viruses to target and neutralize harmful bacteria in a patient’s body. In Greek, bacteriophage literally translates to “bacteria eater,” and the microscopic organisms are found in all corners of the planet.

It’s a method that 69-year-old psychiatry professor Tom Patterson credits with saving his life. He was in Egypt, on vacation in 2015, when he became infected by a severe strain of acinetobacter baumannii, a potentially deadly pathogen in his pancreas.

Wracked with intense pain and nausea, Patterson was airlifted home to California, where he received treatment at the Intensive Care Unit at Thornton Hospital in La Jolla.

That’s when doctors realized his infection wasn’t responding to medication.

“We were confronted with a man who was infected in multiple locations with an organism that was not sensitive to the antibiotics we had available and that we couldn’t drain adequately,” Dr. Robert Schooley, professor of medicine and chief of the division of infectious diseases at the UC San Diego School of Medicine, told CTV News.

Shortly thereafter, Patterson’s condition worsened. An internal drain localizing his infection slipped, causing bacteria to spill into his abdomen and bloodstream. Patterson fell into a coma for two months.

His wife, Steffanie Strathdee, recalled the harrowing time.

“I asked Tom, ‘Do you want to give up, or do you want to fight?’ He squeezed my hand and I knew he wanted to fight,” Strathdee said.

An unlikely solution

While doctors worked to stabilize Patterson’s condition, Strathdee, a Canadian who works as chief of the Division of Global Public Health at UC San Diego School of Medicine, began to research. A friend told her about phage therapy, a concept Strathdee learned about in a virology class at the University of Toronto.

Phage therapy was co-discovered in the early 1900s by French-Canadian microbiologist Felix d'Herelle and widely used at the turn of the 20th century. But it was quickly eclipsed by the discovery of antibiotics in the 1940s and eventually faded from Western medical research and application. However, it remained in therapeutic use in France and the Soviet Union.

With few options available and her husband’s condition worsening, Strathdee proposed the unusual solution to Schooley. They decided to give it a shot.

They received phage strains from from three sources: the Biological Defense Research Directorate of the NMRC, the Center for Phage Technology at Texas A&M University, and San Diego-based biotech company AmpliPhi.

The medical team obtained emergency approval from the U.S. Food and Drug Administration to try the experimental treatment, which must be tailored to suit an individual patient’s case. For Patterson, the phage was administered intravenously and through catheters into his abdomen.

Within 48 hours of receiving the phage therapy, Patterson woke up from the coma.

“We began to see his blood pressure stabilize, his white [blood cell] count begin to come down, and it was very clear that he was having a clinical response to the bacteria phage,” Schooley said.

Three months after receiving the phage therapy, there was no evidence of the harmful bacteria in Patterson’s body. By the fifth month, he was sent home from hospital.

“I’m going to enjoy the rest of my life enormously,” Patterson said.

Phage therapy ‘not simple’

The World Health Organization estimates that antimicrobial resistance will kill at least 50 million people per year by 2050. Researchers hope Patterson’s remarkable recovery story could spark renewed interest for mainstream medicine to explore phage therapy as a treatment against drug-resistant bacteria.

“We’re going to need an additional alternative method of treating deadly bacteria, and so I see phage therapy as a front-runner for that alternate medicine,” said Jon Dennis, a microbiologist with the University of Alberta.

Dennis said Patterson’s case was extraordinary because it was the first time in North America that modern science paid attention to phage therapy as a viable treatment.

“There has been difficulty getting funding to do basic phage therapy research. The problem lies in that a lot of the phage therapy data that we have is historical, it’s anecdotal and it hasn’t been performed in the modern era,” he said.

But phage therapy is hardly a one-size-fits-all solution. Doctors need to create a unique combination of different types of bacteriophage for a patient’s particular case.

“They’re not simple to use,” Schooley said. “They seem to be relatively safe to give, but they’re going to be difficult to develop from both the research perspective, and also from the regulatory perspective, because each patient’s phage cocktail is a different cocktail.”

Despite the challenges, doctors are optimistic that the century-old method could be one way to fight the growing global threat of antibiotic resistance.

Meanwhile, Felix d'Herelle’s legacy lives on. At Laval University in Quebec, a reference centre where scientists can search and order phages has been named in his honour. This year also marks the 100th year since d'Herelle’s discovery, and the Paris-based Institut Pasteur celebrated the anniversary with a presentation of Patterson's case.

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